tbuckley/cabot-search huggingface dataset:
Abstract 3137: Elucidating the role of RNA-binding proteins in pancreatic cancer extracellular vesicle crosstalk
Authors: Jennifer M. Finan, Roberto Di Niro, Randall Armstrong, Jonathan R. Brody
Journal: Cancer Research (2022)

Abstract Many solid tumors, including pancreatic ductal adenocarcinoma (PDAC) tumors, rely on pro-tumorigenic intercellular paracrine signaling during tumor progression. Extensive work has been done to understand paracrine signaling via cytokines, chemokines, and metabolites secreted from tumor cells, but only recent studies have begun to investigate the role of extracellular vesicles (EVs) and their cargoes in the tumor microenvironment. Studies have illustrated the ability of PDAC-derived EVs to activate and recruit pancreatic stellate cells in the tumor microenvironment; however, no work has been done in vivo to determine whether this EV uptake occurs within tumors. Additionally, little mechanistic work has been done to understand the functional consequences of EV cargo within recipient cells. Based on transcriptomic and proteomic analysis of PDAC patient-derived EVs, mRNAs and RNA-binding proteins (RBPs) are enriched within EVs. Our lab focuses on the role of RBPs in PDAC, and thus, we will utilize enhanced crosslinking immunoprecipitation to identify the RBPs within PDAC EVs and evaluate their impact on the EV transcriptome. We have successfully isolated and characterized EVs via size exclusion chromatography isolation paired with western blotting for classical EV markers, fluorescent nanoparticle tracking analysis, and transmission electron microscopy. We have also demonstrated that we can identify mRNA cargoes that are bound and unbound by RBPs. Additionally, we have optimized PKH67 labeling and detection of PDAC EVs to assess specific and preferential uptake in vitro. Further, we are establishing the validated PalmGRET bioluminescent reporter in our patient derived cell lines to track PDAC EVs in a pancreatic orthotopic mouse model. Utilizing this method, we intend to identify cell types in the microenvironment that are importing PDAC EVs and perform functional studies to understand how these cells are impacted by EV signaling. These studies will elucidate which cells in the PDAC tumor microenvironment import PDAC EVs, as well as interrogate the mechanistic role of PDAC EV crosstalk. This work will further characterize the role of RBPs in PDAC and begin to evaluate their role in a cell extrinsic manner. Citation Format: Jennifer M. Finan, Roberto Di Niro, Randall Armstrong, Jonathan R. Brody. Elucidating the role of RNA-binding proteins in pancreatic cancer extracellular vesicle crosstalk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3137.
Abstract 5982: Single-cell RNA sequencing (scRNA-Seq) from mice model reveals metastatic and stemness signatures in esophageal squamous cell carcinoma (ESCC)
Authors: Ching Ngar Wong, Yu Zhang, Beibei Ru, Hong Yu Zhou, Kwong Yiu Lam, Xin Yuan Guan
Journal: Cancer Research (2022)

Abstract Remote oligometastases are the predominant roots of the unsatisfactory 5-year survival rate in esophageal squamous cell carcinoma (ESCC) patients. The title of metastatic-initiating cells (MICs) has been designated to describe tumor subpopulation with heterogeneous genetic background and behaviors that potentially displays stemness features and favors metastatic lesion formation. However, preceding studies have overpassed the early surviving MICs due to limitations in bulk transcriptomic sequencing at macrometastatic stage. With the aim of denoting and characterizing MICs in ESCC, we established the pulmonary metastatic mice model via intravenous injection and followed by multiplex single-cell RNA sequencing (scRNA-Seq) of tumor cells collected from lung tissues along longitudinal end-points. The scRNA-Seq results uncover a 7-gene surface marker signature panel that could depict the early surviving MICs of ESCC, including CD44, TACSTD2, TM4SF1, S100A14, RHOD, CST6, and C19orf33. In silico gene ontology (GO) enrichment of the early surviving MICs subpopulation reveals numerous migration and adhesion-related biological processes (p&amp;lt;0.05). In addition to scRNA-Seq, immunohistochemistry (IHC) staining of tumor cells in mice lungs collected in sequential order evidenced the survival heterogeneity of tumor subpopulations. Likewise, flow cytometry fluorescence-activated cell sorting (FACS) of signature-enriched tumor cells was performed to resemble the target MICs. CD44Pos ESCC cells are found to show distinctively greater wound-healing (p&amp;lt;0.01), foci formation (p&amp;lt;0.05), migration (p&amp;lt;0.01) and invasion (p&amp;lt;0.01) ability than CD44Neg cells in vitro, and longer survival patterns (p&amp;lt;0.05) upon implantation in vivo. Multi-color immunofluorescence (mIF) staining of these gene signatures is underway in mice models and clinical samples for comprehensive validation. We anticipate this surface marker signature to accelerate development for clinical diagnosis together with molecular targeting in metastatic ESCC patients. Citation Format: Ching Ngar Wong, Yu Zhang, Beibei Ru, Hong Yu Zhou, Kwong Yiu Lam, Xin Yuan Guan. Single-cell RNA sequencing (scRNA-Seq) from mice model reveals metastatic and stemness signatures in esophageal squamous cell carcinoma (ESCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5982.
Abstract 6316: Minimizing ineffective treatment using an <i>in vitro</i> patient derived cancer cell screening platform for local oral squamous cell carcinoma patients in Pakistan
Authors: Sabaoon Zeb, Khudeja Salim, Hina Zamir, Madina Shirdel, Momal Agha, Asma Qudrat, Sajjad Ahmad, Muhammad Faisal, Muhammad Atif Munawar, Muhammad Mushtaq Khattak, Mushtaq Ahmad, Zubbair Durrani, Faisal F. Khan
Journal: Cancer Research (2022)

Abstract According to GLOBOCAN’s 2020 report, in Pakistan, lip and oral cavity is the second most prevalent cancer with a low survival rate due to late detection and ineffective treatment regimens. To reduce ineffective treatment, this study aims to develop a cost-efficient in vitro drug screening platform using patient-derived primary cell lines to identify effective drugs against Oral Squamous Cell Carcinoma (OSCC) patients. Chemotherapeutic drugs to be screened were identified from NCCN guidelines as well as the local standard of care after oncologists from three tertiary care hospitals. These included 15 chemotherapeutic drugs along with 14 combinations. For this pilot study, tumor biopsies were collected, after relevant IRB approvals from consenting patients as part of the Oral Cancer Genomics Study project. Patient-derived primary cell lines were generated from tumor biopsies of 20 local OSCC patients recruited at Rehman Medical Institute and Hayatabad Medical Complex, Peshawar, Pakistan. Primary cell lines were derived from tumor biopsies within 30 minutes of resection and propagated till confluency using an optimized DMEM protocol. The readouts of our screen include cell viability, cell proliferation and cytotoxicity. This pilot screen presents a first of its kind dataset of the performance of drugs and drug combinations in primary cell lines derived from the tumors of local patients in Pakistan. This is not just an ideal platform to test novel and re-purposed drugs but also to develop into a service for personalized treatments, minimizing ineffective treatment and improving patient outcomes. Citation Format: Sabaoon Zeb, Khudeja Salim, Hina Zamir, Madina Shirdel, Momal Agha, Asma Qudrat, Sajjad Ahmad, Muhammad Faisal, Muhammad Atif Munawar, Muhammad Mushtaq Khattak, Mushtaq Ahmad, Zubbair Durrani, Faisal F. Khan. Minimizing ineffective treatment using an in vitro patient derived cancer cell screening platform for local oral squamous cell carcinoma patients in Pakistan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6316.
The multifaceted role of platelets in mediating brain function
Authors: Thierry Burnouf, Tara L. Walker
Journal: Blood (2022)

Abstract Platelets, the small, anucleate blood cells that originate from megakaryocytes in the bone marrow, are typically associated with coagulation. However, it is now apparent that platelets are more multifaceted than originally thought, with their function extending beyond their traditional role in hemostasis to acting as important mediators of brain function. In this review, we outline the broad repertoire of platelet function in the central nervous system, focusing on the similarities between platelets and neurons. We also summarize the role that platelets play in the pathophysiology of various neurological diseases, with a particular focus on neuroinflammation and neurodegeneration. Finally, we highlight the exciting prospect of harnessing the unique features of the platelet proteome and extracellular vesicles, which are rich in neurotrophic, antioxidative, and antiinflammatory factors, for the development of novel neuroprotective and neuroregenerative interventions to treat various neurodegenerative and traumatic pathologies.
Abstract 5972: Antiangiogenic activity of FGFR inhibitor erdafitinib in urothelial carcinoma
Authors: Seungtaek Lim, Sun Young Rha, Hyun Joo Bae, Sang Woo Cho, Jii Bum Lee, Tae Soo Kim, Sun Kyung Kang, Woo Sun Kwon, Nam Hoon Cho, Young Deuk Choi, Kunhong Kim, Hoi Young Lee
Journal: Cancer Research (2022)

Abstract Purpose: Fibroblast growth factors (FGFs) and fibroblast growth factor receptors (FGFRs) are implicated in tumor angiogenesis. Although erdafitinib showed efficacy in urothelial carcinoma (UC) patients harboring FGFR pathway alteration, the anti-angiogenic activity of this compound remains uncertain. Here, we investigated the suppression of UC growth by inhibiting angiogenesis with erdafitinib both in vitro and in vivo. Materials and Methods: The inhibitory effect of erdafitinib on UC cells was evaluated by wound healing assay, transwell invasion assay, and zymography assay. Tubule formation assay and transwell migration assay was conducted to assess inhibitory effect of erdafitinib on endothelial cells (EC). Transwell migration assay to assess crosstalk of EC co-cultured with UC cell was also performed. For in vivo study, athymic nude mice bearing RT4 cells were randomly divided into a control group, and erdafitinib group. Tumors were then extracted for analysis such as immunohistochemistry. Results: The results of wound healing assay and transwell invasion assay demonstrated that erdafitinib has inhibitory actions on the migratory and invasive potential of UC cells. Erdafitinib also suppressed tube formation and migratory potential of ECs. Transwell migration assay using EC co-cultured with RT4 showed that migration of EC was significantly inhibited by erdafitinib. For in vivo experiments, immuno-deficient mice (N=14) bearing RT4 xenografts were treated with or without erdafitinib (40mg/kg) orally three times a week for three weeks, and erdafitinib significantly suppressed tumor volumes and weight by 60.0% and 24.4%, respectively. The decrease of both CD31-positive and Ki-67-positive cells indicated that erdafitinib exerted anti-angiogenic activity. Conclusion: This study demonstrated that erdafitinib has anti-angiogenic activities both in vitro and in vivo. It warrants further investigation for development of new therapeutic strategy. Citation Format: Seungtaek Lim, Sun Young Rha, Hyun Joo Bae, Sang Woo Cho, Jii Bum Lee, Tae Soo Kim, Sun Kyung Kang, Woo Sun Kwon, Nam Hoon Cho, Young Deuk Choi, Kunhong Kim, Hoi Young Lee. Antiangiogenic activity of FGFR inhibitor erdafitinib in urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5972.
Abstract LB519: Bimodality of gene expression in cancer patients as interpretable biomarkers for drug sensitivity
Authors: Benjamin Haibe-Kains, Wail Ba-alawi
Journal: Cancer Research (2022)

Abstract Identifying biomarkers predictive of cancer cells’ response to drug treatment constitutes one of the main challenges in precision oncology. Recent large-scale cancer pharmacogenomic studies have opened new avenues of research to develop predictive biomarkers by profiling thousands of human cancer cell lines at the molecular level and screening them with hundreds of approved drugs and experimental chemical compounds. Many studies have leveraged these data to build predictive models of response using various statistical and machine learning methods. However, a common challenge in these methods is the lack of interpretability as to how they make the predictions, hindering the clinical translation of these models. To alleviate this issue, we used the recent logic modeling approach to develop a new machine learning pipeline that explores the space of bimodally expressed genes in multiple large in vitro pharmacogenomic studies and builds multivariate, nonlinear, yet interpretable logic-based models predictive of drug response. We showcased the performance of the approach in a compendium of the three largest in vitro pharmacogenomic data sets to build robust and interpretable models for 101 drugs that span 17 drug classes with high validation rate in independent datasets. These results along with in vivo validation support a better translation of gene expression biomarkers between model systems using bimodal genes. Citation Format: Benjamin Haibe-Kains, Wail Ba-alawi. Bimodality of gene expression in cancer patients as interpretable biomarkers for drug sensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB519.
Abstract 2431: A novel role of MUC5AC/CD44v6/c-Met axis in breast cancer brain metastasis
Authors: Shailendra Kumar Maurya, Jawed A. Siddiqui, Shailendra K. Gautama, Ranjana K. Kanchan, Ramesh Pothuraju, Gopalakrishnan Natarajan, Pranita Atri, Ramakanth C. Venkata, Rakesh Bhatia, Parvez Khan, Asad Ur Rehmana, Sanjib Chaudhary, Naveenkumar Perumal, Sidharth Mahapatra, Hitendra S. Chand, Maneesh Jain, Juan A. Santamaria-Barriab, Diana M. Cittelly, Surinder K. Batra, Mohd W. Nasser
Journal: Cancer Research (2022)

Abstract Brain metastasis (BrM) is one of the leading causes of mortality in breast cancer (BC). Although BrM is associated with all BC subtypes, but it is more prevalent in triple-negative and HER2+ BC patients. Recent advancements in the multimodality treatment of primary BC have prolonged patient survival, which has in turn increased the incidence of BrM. Due to the lack of understanding of BC-BrM, there is no reliable biomarker and effective therapeutic strategy. In this regard, using publicly available databases and RNA-Seq analysis, we observed that secretory mucin MUC5AC is significantly upregulated in BC brain metastatic cell lines and tissues compared to their respective control. We validated these observations in brain-seeking BC (BSBC) cell lines and brain metastatic tissues at protein levels. Interestingly, we found that the MUC5AC levels were significantly increased in the serum of CNS metastatic patients relative to healthy donors and BC patients. Our functional studies revealed that silencing of MUC5AC in BSBC cell lines showed a significant decrease in cell adhesion, migration, brain metastatic potential, and increased survival of mice. Exploring the molecular mechanism further revealed that MUC5AC interacts with CD44v6 and c-Met and deletion of MUC5AC demonstrated a decrease in the expression of c-MET and CD44v6. Furthermore, pharmacological targeting of MUC5AC through c-Met inhibitor reduces the expression of CD44v6 and MUC5AC, suggesting that c-Met inhibitors could be used as a novel therapeutics for targeting MUC5AC and thereby attenuating BC brain metastasis. Altogether, our study demonstrates that MUC5AC/CD44v6/c-Met axis could be used as a novel approach to prevent breast cancer brain metastasis. Citation Format: Shailendra Kumar Maurya, Jawed A. Siddiqui, Shailendra K. Gautama, Ranjana K. Kanchan, Ramesh Pothuraju, Gopalakrishnan Natarajan, Pranita Atri, Ramakanth C. Venkata, Rakesh Bhatia, Parvez Khan, Asad Ur Rehmana, Sanjib Chaudhary, Naveenkumar Perumal, Sidharth Mahapatra, Hitendra S. Chand, Maneesh Jain, Juan A. Santamaria-Barriab, Diana M. Cittelly, Surinder K. Batra, Mohd W. Nasser. A novel role of MUC5AC/CD44v6/c-Met axis in breast cancer brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2431.
Abstract 6106: The effect of neoadjuvant chemotherapy on tumor immune microenvironment in ovarian cancer
Authors: Guangming Cao, Dingchao Hua, Lina Cui, Xiaochen Zhao, Shuzhen Wang, Lei Zhu
Journal: Cancer Research (2022)

Abstract Background: Ovarian cancer (OC) is a highly lethal gynecologic malignancy, neoadjuvant chemotherapy (NACT) with interval de-bulking surgery (IDS) is an established strategy for woman with advanced epithelial ovarian cancer (EOC). Tumor infiltrating lymphocytes (TILs) play an important role in the pathogenesis of OC. However, the effect of NACT on tumor immune microenvironment (TIME) has not been evaluated. Methods: All patients underwent NACT with IDS. Formalin-fixed paraffin-embedded tissue samples were collected from biopsy specimens and the corresponding post-NACT surgical specimens. The densities and percentage of specific TILs [CD8+, CD3+, CD4+, CD20+, tumor associated macrophages (TAMs), dim CD56+NK, bright CD56+NK, PD-1+ etc.] within the TIME were analyzed by multiplex immunohistochemistry (3DMedcines Inc.). Serum CA 125 was measured 3-weekly per protocol and evaluated the response to NACT using GCIG CA125 response criteria. Results: A total of 28 patients were enrolled in this study with planned IDS after NACT. Of 25 patients evaluated by GCIG CA125 response criteria, 76% (19/25) had a CA125 response. In CA125 response patients, we observed significant recruitments of the densities and percentage of CD8+ in tumor, percentage of PD-1+ cell in tumor after-NACT vs before-NACT (34.85/mm3 vs 110.54/mm3, p=0.0258; 0.50% vs 1.73%, p=0.0132; 0.53% vs 2.66%, p=0.0576, respectively), while no significant change was found in TAMs, NK cells and CD20+ cells. However, in CA125 non-response patients, the TILs in tumor did not change significantly. Conclusion: NACT could release the tumor associated antigen by killing tumor cells for uptake by tumor-infiltrating dendritic cells and promote the infiltration of CD8+ and PD-1+ T lymphocyte in CA125 response OC patients. Given the limited clinical prognostic information and the number of patients in this study, the results of this study will need confirmation in larger studies in the future. Citation Format: Guangming Cao, Dingchao Hua, Lina Cui, Xiaochen Zhao, Shuzhen Wang, Lei Zhu. The effect of neoadjuvant chemotherapy on tumor immune microenvironment in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6106.
The prevalence of frailty and pre-frailty among geriatric hospital inpatients and its association with economic prosperity and healthcare expenditure: A systematic review and meta-analysis of 467,779 geriatric hospital inpatients
Authors: Paul Doody, Evans A. Asamane, Justin A. Aunger, Bridgitte Swales, Janet M. Lord, Carolyn A. Greig, Anna C. Whittaker
Journal: Ageing Research Reviews (2022)

Frailty is a common and clinically significant condition among geriatric populations. Although well-evidenced pooled estimates of the prevalence of frailty exist within various settings and populations, presently there are none assessing the overall prevalence of frailty among geriatric hospital inpatients. The purpose of this review was to systematically search and analyse the prevalence of frailty among geriatric hospital inpatients within the literature and examine its associations with national economic indicators.Systematic searches were conducted on Ovid, Web of Science, Scopus, CINAHL Plus, and the Cochrane Library, encompassing all literature published prior to 22 November 2018, supplemented with manual reference searches. Included studies utilised a validated operational definition of frailty, reported the prevalence of frailty, had a minimum age ≥ 65 years, attempted to assess the whole ward/clinical population, and occurred among hospital inpatients. Two reviewers independently extracted data and assessed study quality.Ninety-six studies with a pooled sample of 467,779 geriatric hospital inpatients were included. The median critical appraisal score was 8/9 (range 7-9). The pooled prevalence of frailty, and pre-frailty, among geriatric hospital inpatients was 47.4% (95% CI 43.7-51.1%), and 25.8% (95% CI 22.0-29.6%), respectively. Significant differences were observed in the prevalence of frailty stratified by age, prevalent morbidity, ward type, clinical population, and operational definition. No significant differences were observed in stratified analyses by sex or continent, or significant associations between the prevalence of frailty and economic indicators.Frailty is highly prevalent among geriatric hospital inpatients. High heterogeneity exists within this setting based on various clinical and demographic characteristics. Pooled estimates reported in this review place the prevalence of frailty among geriatric hospital inpatients between that reported for community-dwelling older adults and older adults in nursing homes, outlining an increase in the relative prevalence of frailty with progression through the healthcare system.
Re: J. Alberto Nakauma-González, Maud Rijnders, Job van Riet, et al. Comprehensive Molecular Characterization Reveals Genomic and Transcriptomic Subtypes of Metastatic Urothelial Carcinoma. Eur Urol 2022;81:331–6
Authors: Yuxuan Song, Caipeng Qin, Tao Xu
Journal: European Urology (2022)